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    • 专利摘要:
    A method for producing benzo (c) quinolines of the general formula O OR 1 Z-W wherein R is acetyl or 4-H-piperidylbutyryl; RJ is a Ci-Cj-alkyl moiety (CH) ,,, where Z is 1, 2; Z-W-C-Cj-alkyloxy- or C-C alkoxy; RJ is a hydrogen atom, methyl, isobutyryl, benzoyl, or their salts with pharmaceutically acceptable acids, characterized in that the compounds of the formula II OH O) r-w 1C where Rj, R and ZW have the indicated values, are subjected to lithium reduction ammonia, followed by acylation of the resulting compound and the desired product, in the free form or as a salt with pharmaceutically acceptable acids.
    公开号:SU1124887A3
    申请号:SU782664051
    申请日:1978-09-18
    公开日:1984-11-15
    发明作者:Росс Джонсон Майкл
    申请人:Пфайзер Инк (Фирма)；
    IPC主号:
    专利说明:

    1 eluent, which is concentrated to sublumine-purple compound (580 mg) under reduced pressure and triturated in a benzene / ether mixture (1: 1), gives 370 mg of a solid compound; t, pl.154. It is stored under nitrogen and in the dark. The isolated substance is a mixture of cis- and trans-isomers of the indicated compound rVe- 345 K 1 H, NMR (100 MHZ), lyle / ppm: 6.85 and 7.49 (1 H, ac 5.67, 5 , 71; 5.85; 5.93 (d., 1 2H2, 2H poly., Aromatic, hydrogens in ais / trans mixture), 0.90 (t, ZN, terminal CH), 1.12-4, 43, (Ie remaining H). P me R 2. Isomeric 5,6, s (, 7 10,10 ° (-gvsagidro-1-acetoxy-6 / s-methyl-3- (2-hepshx 10 d benzo (s ) quinoline9 (8S-ony. 2.2 ml of pyridine was added to a suspension of 5.6.6 °, 7.10, Yu-hexahydro1-hydroxy-6 methyl-3- (2-heptsyloxy) benzo (c) quinolin-9 ( 8U it (222 mg, 0.642 mmol) in acetic anhydride (2.2 ml under nitrogen atmosphere. The mixture is stirred in t 1.5 h at room temperature and then poured into ice (50 ml. The resin is isolated and extracted with ether (3 x 50 ml) and the combined extracts are washed first with water (4 x 50 ppm) and then with a saline solution (1 x 60 MJ. The extract is dried ( MgSOv) and reduced under reduced pressure to a red oil (250 mg). The oil is dissolved in a minimum amount of hot ether and a 0 column of silica gel (45 g) packed and washed with a mixture of pentane / ether (3: 1) is introduced. The column is washed with a mixture of pentane / ether (3: 1, 200 ml), the Elution is continued and collected. fractions of 10 ml each. Fractions 2232 are combined and concentrated to obtain a foamy compound (113.5 mg), which crystallizes from petroleum ether as white crystals; mp, 112-114 °, Fractions 33-35 are combined and concentrated to a foamy compound (89.7 mg), which is recrystallized from petroleum ether as white. crystals; t, mp, 78-82 ° C, the Products are isomeric mono-acetylated compounds, Example 3 d, f-5,6, 6-7,10 J1 Qet-Gek sagidro-1-acetoxy-6-methyl -3- (2-heptyloxy) benz o (c) quinoline-9- (8H J-it G 74 22.2 g a, -5.6-, d, 7,10,10y hexahydro-1-hydroxy- 6/4-methyl-3- (2heptyloxy) benzo (c) quinoline-9- (8H) it is directly acetylated, in a final solution 2.35 g of acetylated product are obtained. The product is carefully ground in a mixture of pentane / ether (3: 1 ) until a tan solid is obtained (905 mg) which, upon further recrystallization from ethanol, produces light brown kr istallov; t, pl 112113, 5C, the mother liquors from which the compounds are isolated are combined and concentrated. The residue is dissolved in a minimum amount of a mixture of benzene / ether / methylene chloride (1: 1: 1) and introduced into the column with silica gel (275 g), eluted with petroleum ether / ether (3: 1), first elution was carried out with 2 l of petroleum ether / ether (3: 1), ja then; 1.5 l petroleum ether / ether (2: 1) and 2 l of a mixture of petroleum ether / ether (1: 1). Fractions 2-11 (50 ml each) of the eluate from the 1: 1 solvent system are collected and concentrated under reduced pressure to obtain a foam-like product (496 mg). After crystallization from petroleum ether, white cristagles are obtained; t, mp, 100-113 ° C (410 mg). After recrystallization from ethanol / water (1: 1), d, it-5 -6.6.6 p-7.10.10 ° (- / 3-hexahydro-acetoxy-6 - methyl 3- (2-heptyloxy) benzo (s) -quinolin-9 (8H) -one; mp. 11112 ° C, t / e-387 (t-). Calculated%: C 71.29, H 8.58, N 3.61: Found,% C 70.95; H 8.64; IN 3.58. Fractions 12-18 and 19-27, 50 ml each are collected and concentrated to give 273 ml and 208 mg corresponding to the acetylated product. After crystallization of the residue of fractions 19-27 from petroleum ether, white crystals (119 mg) are obtained, m.p., mp, 84-88 ° C. After recrystallization from ethyl acetate / hexane (1:10), d, -cis-5 are obtained , 6 , 6E1CD, 7, 10,10a / 5-hexahydro-1-acetoxy-3- (2heptch1oxy) -6 3-methylbenzo (c) quinoline9 (8H) -one; mp, 84-86 C. Calculated,%: C 71.29; H 8.58; N 3.61
    Chz
    11th,%,%; C 7 i, 05; And I, iB; N3.56
    Analogs:; in a way nfijivsiaioi and-, corresponding to Str. 5; ledued-ig;,; -; Connected
    d l-rpaTIc-Sjfe ,, 7, 10, 10rtf / if4;
    Sagidrs 1 -Acctogssi-6 /:) - part of (iLn 3- (6-feni.n - 2--1te1-5thyloxn) ben: k; (c) hi1G ;;, ;;; gn-9 ( 8i) -op t. VTji,, I ofSS (PM,
    Psrcchi ano%; C 7 4., I; D 7) -t; N 3.22
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    ace to; /; - nb-, jp,
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    N 2.97,
    fU --.:-Ji,C-5,G,6e(,u7, iO, Kb -.: ...:,;.,;..
    sagp.) - -, ccepksi - 3- (5- diei-ii-jT-vneKTiij7OK-i 2 6 / Г1по; n rbg: -g;, d (c) hi, sm 9 (8li) -oHj ,, iu:., 79 - -ft3 Gt-.) u DD /: ;; s-- 2., u-ip. lis | 0ai.; h - 1. {;;:. -H- (j - ibetO-ijr -,: - Tii i; t, n; kg.) in..jrn-; j (6eK3 ;: i (c)
    (SH) -OI; t-, gg. ; D. ; : .6-G; :; id, - gp
    pi lie; - 4-: (PG),
    d-cis- ,,., 7 „; 0. ; -C /: 1gd
    gray-11 baby: pci: on with ;; hepodi -
    he, g j..f, 90 (c:; 1РЧ .-; o :: d LIDR; P: n: CDDSHD / S-it;; m: G,
    lots.
    N. 9 7
    ;.,, | .; . ,, 0 ,.
    Id: sno,% - C 64.2 h; And 7,: 0 N3.01.
    H G1; a years: -, 6. 6ciff., /, K ;. I Oir - iKCH1 -aueTCiOCH - З- (5 - frti1 g 2 h ii i.:n;:K;;t2
    6 / J MCTKJ-t6SHSo (c) HYPODIES T (Bfij / h J
    t PL „90-95 ((; times ifwcciniev.:; ь. ode S0.- HURDD: .POPRO; 10Kk, D
    Loil
    PI - 3 „j. B gz; 7, K), 1 Oy-Hexagid1 -. IuOToKCvi - 3-v5-feni. - pinch; --h / a crt1peizs (d-) hipo-hshi-9 (8H) -one J- /; 7i-92 C in h1-: dehydrated, i-r; -20.2С (g - o, 19, CHjOH). -if i-- but,%; C 68L1; And 7.26;
    С ,, dT „0,1-tС
    Iaideio,: Ñ С 6Я.-2; H 7.23:; dd,
    --1J - HC-T.Djoa / i., 7; 0j (Och / h-TexaM) - - l up to 7 (zhsi- -Z-S 5fekid-2-pen: i iU .nfJeif3o (c) hiiolin-9 i.-f-, 1D1Sh, 92--37 2 in pid hlorNS
    , 6, Sw-, iOj: K-BR: -methyl
    hell 7 where
    c) hee
    CCH
    : --- VO) i; -o ;, vd.: - and DIS-ISS. i 1: 7;). d) i -) -. (; T ke .io-.cv) :: 4 {uo p i- ,. : P.pameD.:; .- 1. rHH RSHG (D.DUK- Ko. (In
    -xibcpc, -; Ji shabzheigyu njexa .t: x;.; - v: -;: 1: mt7koy, SCO ppm capep
    , A; ie, they place:; -Dock: 2.2 g) dreuk :) u1D) dk V; undoubtedly in -: -; - dd: xd; t ori (color, K l -1O; and:; l7K :: x; y sp .-- 1y pricTBOpy poi,. gd 5,1-JJ 6; 5 - tetra-G -1- 1: gs-o; -; Etil-3 (5 - fennl-2- ;;; ..d: i; 0sch :: dis) chi; dtid -9 (8H) -on; /: -K11du - 1D1C-s; oreny in 2- .1D: D.Fut; G;:; i 250 h: e) kagg.p m -SiiiiTp in ./; .;, Posde ds17dgnitel :; doromcia-cd1i (1P min) at -78 ° 1: to duggs f-Me..b cutting is cooled to: (r: t.; -; :: Hb M; d), ddgrstvom chloride -iT 7-Hi -, ; Then, oh, a fitment: ;; D1 P1 l rekl (1) -th {nuo mixture of honey ::. Red ;;: floor and steam 5a; t for rehpd 1D1: DI. Cgda ok almost. ds.ifits doaa11; pcs of pettilatas -: f; v (1 l) and: MtJCb ne / p ;; - g;: g;: for g t, t; - np11ne Pmin, then dod ;. - 7 C.L01D norjiiyk; FPU is still reehirgut gidad: Tggo | A (ZO ml), 5. (;;;....... id: dd de extraggi 7 washed again with water (1 l), dried (MgSO4) and concentrated to brown semi-solid state (g) The residue obtained is immediately dissolved in methylene chloride (200 ml. 4-dimethylaminopyridine (.7.5 g, 0.061 mol) is added and triethylamine (6.1 g, 0.061 mol) is stirred and the solution is cooled to ( ice / water refrigerant) under nitrogen atmosphere. Then, with vigorous stirring, acetic anhydride (6.1 g, 0.061 mol) is added dropwise for 5 minutes. After stirring for an additional 30 min the ionic mixture is diluted with ethyl acetate (2 L) and water (1 L) and stirred for 10 minutes. The aqueous mixture is extracted once more with water and the combined organic one; e extracts are successively washed with water (4 x 1 L with saturated sodium bicarbonate (1 x 1 L), brine (1x1 L), dried (MpO) and concentrated to a light brown oil (27 g). The residue is purified on an IjS kg silica gel chromatography column using benzene 15 / ethyl acetate as an eluting solvent. I collect fractions of 1 l. After elution of the less polar impurities, fractions 16-20 are combined and evaporated to a residue, which is then crystallized from ether / petroleum ether to give 5.6 g (22.4%) of the trans isomer of the indicated product. Fractions 21-27 are combined and 7.6 g (31.8%) of a mixture of trans and cis isomers are obtained, and fractions 28-32 are combined and 7.6 g (31.8%) of a mixture of trans and cis are obtained. isomers, fractions 28-32 are combined and 2.5 g (10.4%) of the cis isomer of the compound is obtained. Characteristics of the trans isomer: m / e 435 (t). , H 5ШР (60 MHz), (cDMe ppm: 7.24 (p. 5H, aromatics); 5.97 (p., 2 meta-KS); 2.28 (p., 3N, CH3-COO ); 1.23 (d., 3N, CH, CH-0-), 1.20 (d, 3 GHj-Cff-N) - 1.3-4.5 (m. 17H, other protons) , T. Ill. 81-83 C. Calculated,%: C 74.45, H 7.64, N 3.22. Found,%: C 74.15; H 7.68; N 3.18. Characteristics of cis- isomers: We — 435 (m). 78 Mp. of HC1 salt 172-176C- (with decomposition) (from acetone / ether mixture). Calculated,% t С 68.71; H 7.26; N7 07 - C.7H5EO, ShS1 Found,%: C 68.86; H 7.16; N 2.97. PRI me R 5. d, J-5,6,6ei-7,10, 10 "-H-Hexahydro -1-acetoxy-6 / -methyl3- (4-phenylbutyloxy) benzo (c) quinoline9 (8H) -one, cis- and trans-isomers. In accordance with examples 3d, t5, 6,6a | 7-tetrahydro- 1-oxy-b mark l (4-phenylbutoxy) beiso (c) quinoline-9 (8H) -one is first reduced with lithium and ammonium, and then acetylated to obtain the desired hexahydro-isomer. Selection on a chromatographic column with silica gel using ether as the eluent results in a first d , K-trans-5,6,6a, 7,10 10Ahexahydro-1-acetoxy-6 / methyl 3 (4-phenylbutoxy) benzo (c) quinoline-9 (8B) -one; m.p. 155-15b With, after recrystallization from a mixture of ethyl acetate / pentane (1: 5). Calculated,%: C, 74.08; H, 7.41; N, 3.32. CjtHg Q N Found,%: C 74.00, H 7.47; M 3.22. t / e - 421 (t). Further purification of the last fractions on a silica gel column using a mixture of cyclohexane / ether (1: 1) as an eluting solvent yields isomeric d, f-uHC5, 6.6c (/ s, 7,10,10a-hexahydro-1 -acetoxy-6 p-methyl-3 (4-phenylbutyloxy) benzo (c) quinoline-9 (8H) -one, mp.9596 ° C after recrystallization from ethyl acetate / hexane (1: 5), ha / e 421 (t). Calculated,%: C, 74.08, H, 7.41, N, 3.32.C.N. Found,%: C, 73.95; H, 7.51; N, 3.31. Analogously to Example 5 receive the compound shown in table 2, PRI me R 6, d, f-5,6,6a, 7,10, 10-Hexahydro-1-acetoxy-3- (2-heptylok si) benzo (c) quinoline-9 (81) .-- it. Solution d, f-5,6,6n, 7-tetrahydro-1-hydroxy-3- (2-heptyloxy) benzo (g) quinoline -9 (8H) -one (9.0 g) in tetrahydropyb, h :: - ((You h: O: 1ICCh iib: i-ikp; to byGSgg; O rTl ::, KMO; rn-fFi 1 V IJHC IfJU i;., 4 ;; tn (o, 1;) ojiiv- M;) mmk:; ko (. During the nanosm;; |; Cc:; VHi-i d (1b. Ppodo- UGH NIGe. PINN Ojl V jnri-ln ll ;; i 4.aCTHr-i for the contraction of CiiHor; -;, C -. E ;; |, nsyj-Mv; C; C; i HBa; or P (.c. 10 -. iHii ,, -nthem pr; with i Liop jnecuHc i-iBf-mT, up to - :; al; -g /:. excess x ... D) C | 1C; o: o:; m; –yun1 (, (v; night pmmmss is given zohmo; k ;;; :: M; R.splpT-TThfia) l ocTajOi;:;: p; l-state g-sms ; h, oxen; G 3i4-r: U.nvaT; iTa, O | L, CHKICHSS.K1...L layer stdsl Yul Bo, L3m ;;;l,: EK.SGP; LH trU 0:) G.I.GGGRGRGRUGG1M , (J jO Nnel; b, h, t; 1-p: hl lt tpl-p-lpot with water., B-.ni:iT,: from half to half ligg B,; 5:: ro: -l -.po.v; -Ti ;; -l, l) pk:; l1y: ;; l tlS | :: d:: l;: old; lg | C (. M;: ol1LG: m (1 ° Ggkchd CC:, (. G;: icueiy, ;;: v;: r l) GULSHGSIS. | l chL.} GLE Freaked; -LG V; L; LI: jTHf-fe i rf-i -y.byach lltl / l-lm (and ..;) l., 1L: MGL-0, tl.;, 72 ML),: v-TL :; -.L d. -. 22 ::,. D5 soy :: i yut u ;.ch.ap in ;;;:, c, nc.riy cho-pg 2.69 g (26%) li ci iis-vi 1b ..: s; o ;, which-g.: 1.:; -; th :: t; (o (uii4., Method, i-j; d-), :,. 6-, / -g;.:}; O; idr --- 1 l; gi. / D:;,: - ----.tT Oicrii-L-- l: l, s i-lolg ;, ri / s - and / i (-l). L: s: f; l; -,) s,:; y D 7: d18; 1 7.41;: - l-. (and,:, , t) j; -l: yi. C 1: i; if, 5 s; i J .. O .. l.-m.-) Ll.6a, 7, Il I} -.:/;-- 1oxa - ,. About 1L l- / l 1, P; i к - (7 Ы Л f j;. ,, (;; Т ТОТ
    lll: lt:; l: d.: .m; lgll, -l: g; j; nd. ,,. .,., l: d;. „,. ,,.; , j
    : ..; , lllp ..: U: OL-- .., :: l .- .: lrdl :), lllp, c-meDlllll; l .l :(; -O L - :: - ;, ,: ..; .. (Ch. ,,,,;,: -; - j Г f Л i Л1 ,., f, С С И) Л 3 Н 3 О Фрдь.:;. Ллл: .. ,, I L): dm:; / - -l ;. Soil, d: {Я10g l; :: o :: sh- i rd-ull for lp; .Л; Л, КОЛ (ЛЛ :: (- 11 Л ,,; -.: и д9,, - (5д ; ds Li lIlv-: l, -lJ: 1.l: -J-: (MT) Frglll: l-lg - ;; 90 --EDPGTYaYuL:, 5с цектр: рлог лолол-г / odt 0 d S g .:; oo-oh ogogo 1 l -1: cho; -gd,:.; -lgzhnoNoO soyediponi in ntgd gll; -l; lh for DjlIl-nlak it) to-1L | hromdt; .- gro . Filoo, -kop koloi-d, -l ;: yk, dddd; and l (.l1ud; lichyly llOi: l; (llldo U5asdl m / i - 5 :) (rn), IKSsPS id-d:. G: algo, s-0) - - -5 dksaglg rl- 1 1 J. O. O L -:, -l l-ll l - f: ll; d - 2-pen1: -l; (: l ate) Y -; :: lpd .-: n- 9 (OH he,. D-. | 0d-.l,.: y; P () HANDSCHL-LYAT DUTS, ,,,.,.;; lr-glgo-Dlaoro.; ld.;.; school; 7lda1-lge ldllki: 10blu: L1Ya | X selley l 1 ZLHL-: L. KLLU DUT LL.;: NSCHIJA, V: p k .; o l 7.: 1; L-grags-5. 6, Y; -; /,., IО / i С ,. ., d dale; agidrs-L-yutoksD- (--LLg / l, 5 - O.goi.ch-l, ;.-.- mrtyylDlloOS l); l1 1olln-9 (Y:) - he. K perll: l: gl1-l-ld, y tp; ltuktu lrn n ddra 3 ci, l-chow ns - 5, 9.,:. i (gdks i -acs then; hsi-b ;; ch d - {l -} - (2- | - (: LLLg,; tokoud) psdz (PSd g.zollchlch-dkh & goku (819. lg);. 5 l1 lilyl, l; and the subalm smoker d91 ml i
    11 1
    in 5 ml of chloroform. After 2 hours, the reaction mixture was poured onto ice and extracted twice with ether. The combined ether extracts are washed with water, sodium bicarbonate, dried (MgSO;), and filtered to give, after crystallization and crystallization from ether / petroleum ether d, -TpaHC-5,6,6a / J, 7, to, U.S. hexahydro-acetoxy Z-C3-heptyloxy) 5-benzoyl-6 /} - methyl-benzo (c) quinoline-9 (8H) -one m.p. 108-11 (f С, m / e 491 (t).
    By repeating this procedure, using equivalent amounts of acetylene chloride instead of benzoyl chloride and the corresponding benzo (c) quinoline, the following compound is obtained: d, Ptrans-5, 6.6 cc, 7,10,10 ° "-hexahydro-acetoxy-3- (2 -heptyloxy) -5-acetyl-6 -methylbenzo (c) .quinolin-9 (8H) -o sh / e - 433 ().
    For example, d, 8-trans-5,6,60 / a7, 10,10a-Hexahydro-1-acetoxy-6-isobutyryl-3- (5-fench1-2-pentsh1oxy) benzo (c) quinoline-9 (8I) - he.
    A solution of isobugril chloride (I5 mg, 1.07 nol) in chloroform (20 ml) is gradually added with stirring to a solution of d, t-TpaHc5, 6.601 / 4,7,10,10c N-hexahydro-1 acetoxy-3- (5 -phenyl-2-pentsh1oxy) benzo (c) quinoline-9 (8H) -one (450 mg, 1.07 mol) in dry pyridine (1.5 ml) under a nitrogen atmosphere. The reaction mixture is stirred for 5 hours and then poured into ice / water (50 ml), the chloroform layer is separated and the aqueous phase is extracted with chloroform (2 x 20 ml). Chloroform extracts are combined and washed with 10% hydrochloric acid (2 x 10 ml), then with a 1F1 solution (1x10 ml) and dried (MgSO4). After concentrating the chloroform solution in vacuo, a yellow oil is obtained which, upon standing, solidifies. - Sano gives white crystalline. a substance that is isolated by filtration and dried (400 mg), t, rot, 128129 ° C. Concentration of the hexane filtrate gives 121 mg of oil.
    EXAMPLE 9, d, -TpaHc-5,6,6eip 7,8,9,10,1 OaoL-Octagidrb-1 - (4-H-piperidyl butyryloxy) -9-hydroxy-6, | gmetil3 (5-phenyl-2-pentyloxy) benzo (c) hiiolin hydrochloride.
    488712
    To a solution at 25 C d, B-TpaHc5, 6.6 "/ e 7.8,9,10,1 Ovub-octahydro-1,9 dioxy-6 / meth-1-3- (5-phenyl-2-pvntyloxy) benzo (c) quinoline (1.0 g, 2.53 mmol) in methylene chloride (20 ml) was added 4-N-piperidylbutyric acid hydrochloride (0.524 g, 2.53 mmol) and dicyclohexylcarbodiimide (0.573 g, 2.78 mmol ), The reaction mixture was stirred at 25 ° C for 6 h, then cooled for 12 h and filtered. Evaporation of the filtrate and trituration of the residue with ether gives 1.3 g of solid salt and monochloropropane,
    IR (KBr): 2.95; 3.60; 5.65 (ester, c “o), 6.13 n 6.27ja.
    Preparative thin-layer chromatography of a portion of a solid compound on silica gel with tolcine of 0.5 mm and 10% methanol / methylene chloride was used as eluant to give the free base d, t-TpaHC-5,6,6ef / 3,7,8,9,10, 10ot-octahydro-1 - (AH-piperidylbu-h tiryloxy) -9-hydroxy - 6 e-methyl-3- (5-phenyl-2-pentyloxy) benzene) quinoline.
    H NMR (60 Hz), J, h / mpa: 1.12 (d ,, C-3 me-ys side chain); 1.25 (d, J-6HZ, C-6 methyl); 5.84 (s., Two AChN) and 7.16 (s ,, 5H),
    After treatment of the free base with an excess of hydrogen (hpornstbhh) in ether, dehlororhydrate is obtained as a hygroscopic blemish.
    EXAMPLE 10, d, f-5.6, 75 Tetrahydro-1- (4-piperid1 Shbutnr "loxy) -6p-methyl-3- (5-phenyl-2-pentipoxy) benzo (c) quinoline -9 (8H) -one
    To 23 ° С to d, t-5,6,6isi, 7-tetrahydro-1-hydroxy-6/4-metsh-3 (5-phenyl-2-pentyloxy) benzo (c) quinoline-9 (8H) -one solution ( 550 mp, 1.41 mmol) in methylene chloride (26 mp) were added 4-M-piperid1H hydrochloric acid hydrochloride (291 mg, 1.41 mmol) and 5 dicyclohexnylcarbodine imide (3.19 mg, 1.55 mol). The reaction mixture is stirred for 18 h, then cooled to. and filtered. After evaporation of 4l1ltrate and thzal digestion of the residue with ether, 800 mg of d, f-5.6.6 "(, 7-tetrahydro-1- (4-H-piperidip & 1-phyloxy) -6) -methyl-h3- (5-phenyl -2-pentyl oxy) benzo (c) hiiolin-9 (8H) -one chlor5 hydrate as a hygroscopic yellow product, f,
    JC (CHC1e): 2.92, 4.14 (5.69 (e. Ether); 6.00; 6.20 and 6.40.
    Aiologic) 1 way chlorine salts d, -rans 5 5 6, be p, 7; 8 5 9., i C, 1 Oad 6 octagidro - 1 - (AH-morpholinbutyri. Goxy) 9 hydroxy-6p-methy. (5 phenyl 1 -2-pentipoxy) benzo (c) chicoline is obtained from 4 - H - morpholinomasl 1-th axes and d S f Trans - 5 5 6, bn / j, 7, 8, 9.10,1 Cad octahydro-1 ,, 9 - dihydroxy-6p-methkl-3- (5-fet1yl 2- -pentyloxy) benzo (c) quinolica ,,
    IR (KBg) 3.00, 3.75; 5.67 (words "efr1p, 6; 15 and 6., 30
    12488714
    / And, mark; rb-; ; lu (with 3li, aietate Me); / L) 2 and (Us ,, ZI, amide Me);
    (2l., 31Г S.Me); K12
    Uou.oOif, iM o6pa3 (jM df --CIS-5 5 6 5 6a (3, 7 1 Osg-hexahydro - 1-aletoxy-6 / 5MeTT; ji ---- (5-11) ei.n- 2-hcheggti1oxy) bengo (c) hiioli: - 9 (converted into t-cis-b, 6 J oa / Oj 7, rssl-hexahydro1 -adstoxy-5-acetyl-6fi-methyl 3- (5F e h-tl - 2 - lentyl a to s with: n) o n o about (c) x to n on l and n 7; 10, 10ac / - Teksahydro-1 -petilrksi5-acet-11L-6, |} - meth-ip-3- (kil 2-pegg thyloxy) benzo (c) quinoline-9 (8H) -one.
    Gastrite 3.49 g (0.008 mol) d, e-trans-5, 6. Be / 5 5758.9, 10, 1 Ois-octagidro-- (-pytoxp-6 (3 - methyl 3- (5phen1-sh-2-yentoksg) -benzo (s) 9 (8P) - opa in 20 ml is released ; 1 chlorine-free alcohol; the solution is cooled with an ice-water bath, then - пи pyridine (extruded over tablets with gd-tdroxidium cal1-1) „0.95 un (0.013 mol) aij.eTHjchloro1-1da, which is dissolved B 5 ml of chloroform. Then the Omogenic solution at the room temperature is stirred for; 8 hours. The reaction mixture is discharged ;; 50 ml is heated every second; - extracted with chloroform. 25 ml each time, Combined organically. niiOMbmatOT 25 ml n of an all-6t-sp6oiata-sodium solution, 25 ml of podi, 25 ml of brine, dried over sodium sulfate and filtration and evaporated to dry under a pressure of 100 ml of chromatography (200 g Sigcagedt, Brinkman, a sample, a sample, a sample, a glyceride, chromatograph (200 g Sigcaragedt Brinkman, 200 g, Brinkman), and a sample of the MfirabW chromatography (200 g of Brinkman, 20 g, Brinkman, is applied to noMfirabW chromatography (200 g Sigcagedt, Brinkman, GCI). ether 1) lo
    give 2.20 g (yield 83.8% of the target s.oed.Net) and „
    Calculated,%: C 72.90, H 7.39; N 2.80.
    Found,% t C 72., 69; And 7d8; N 2.49
    IR spectra (KVn), m: 2.90 (m); (with); 3.48 (s); 5.62 (s); 5.78 (s); 6.00 (s); 6.15 (s); 6.30 (s), M / e - L77 (MO.
    -H NMR (60 MHz) ,. 7.20 (m., EN, apof-fj; 6.53 (s-2); i, 39 (d., 1I, s-4); 7.41 -), 08 (m ,.
    15
    Td-layered chromatography, benzene / eLf mixture (1: 1) Calculated for%, H sO | 1HC1,%: C 68.71; R 7.26, H 2.96,
    1124887 “6
    Table 1
    Continuation of table 2
    n nt
    a
    to
    R you d ech
    i., .... ,,,.,
    "Rj t: c :;
    权利要求:
    Claims (1)
    [1]
    A method of obtaining derivatives of benzo (c) quinolines of the general formula!
    where R 1 is acetyl or 4-D-piperidylbutyryl;
    - C-C 4 -alkyl or (CH ^), - C ^ H ^, where Z is 1, 2;
    Z-W is C-Cg alkyloxy or C ^ -C $ alkoxy;
    R 3 is a hydrogen atom, methyl, isobutyryl, benzoyl, or their salts with pharmaceutically acceptable acids, characterized in that the compounds of formula II where Rg, R * g ZW have the indicated values, are subjected to reduction with lithium in ammonia, followed by acylation of the obtained the compounds and the target product are isolated in free form or as a salt with pharmaceutically acceptable acids.
    SU ,,,, 1124887 of the general formula
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    同族专利:
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    CS241466B2|1986-03-13|
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    JPS6023112B2|1985-06-05|
    ZA772899B|1978-04-26|
    BE854655A|1977-11-16|
    JPS5653657A|1981-05-13|
    SU940646A3|1982-06-30|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4228169A|1979-06-26|1980-10-14|Pfizer Inc.|1,9-Dihydroxyoctahydrobenzo[c]quinolines and 1-hydroxyhexahydrobenzo[c]quinoline-9-ones as antiemetic agents|
    US4351833A|1980-07-28|1982-09-28|Pfizer Inc.|9-Amino-1-hydroxyoctahydrobenzo[c]quinolines and derivatives thereof as analgesics and anti-emetics|
    US4309545A|1980-07-28|1982-01-05|Pfizer Inc.|Oximino-1-hydroxyoctahydrobenzo[c]quinolines and derivatives thereof|
    US4320124A|1980-10-17|1982-03-16|Pfizer Inc.|Composition for enhancing binding of a benzodiazepine to central benzodiazepine receptors and use thereof|
    US4406888A|1981-01-09|1983-09-27|Pfizer Inc.|Aqueous micellar solutions of levonantradol and N-methyllevonantradol and lyophilic forms thereof for reconstitution|
    US5605906A|1995-03-24|1997-02-25|Merck Frosst Canada, Inc.|Cannabinoid receptor agonists|
    CA2565321A1|2004-05-25|2005-12-08|Othera Pharmaceuticals, Inc.|Oculoselective drugs and prodrugs|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US68733276A| true| 1976-05-17|1976-05-17|
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